Risk‐based versus universal PrEP delivery during pregnancy: a cluster randomized trial in Western Kenya from 2018 to 2019

Abstract Introduction Integrating pre‐exposure prophylaxis (PrEP) delivery for pregnant and postpartum women within maternal and child health (MCH) clinics is feasible and acceptable. It is unknown whether a risk‐guided model would facilitate appropriate PrEP use among MCH attendees better than universally offering PrEP. Methods The PrEP Implementation for Mothers in Antenatal Care (PrIMA) study was a cluster randomized trial to assess two models for PrEP delivery among pregnant women seeking routine MCH care at 20 public clinics in Kenya between January 2018 and July 2019 (NCT03070600). In the Universal arm, all participants received PrEP counselling and self‐selected whether to initiate PrEP. In the Targeted arm, participants underwent an HIV risk assessment, including an objective risk‐scoring tool and an offer of HIV self‐tests for at‐home partner testing; those determined to be at high risk received a PrEP offer. Participants were followed through 9 months postpartum. Primary outcomes included incident HIV and appropriate PrEP use (defined as PrEP uptake among those at high risk and no PrEP uptake for those not at risk). Outcomes were compared using intention‐to‐treat analyses, adjusting for baseline HIV risk and marital status. Results Among 4447 women enrolled, the median age was 24.0 years (interquartile range [IQR]: 20.9, 28.3), and most were married (84.8%). The median gestational age at enrolment was 24 weeks (IQR: 20, 30). Women in the Targeted arm were more likely to be at high risk for HIV acquisition at baseline (51.6% vs. 33.3%). During 4638 person‐years (p‐yr) of follow‐up, there were 16 maternal HIV infections with no difference in maternal HIV incidence between arms: 0.31/100 p‐yr (95% CI: 0.15, 0.65) Targeted and 0.38/100p‐yr (95% CI: 0.20, 0.73) Universal (adjusted relative risk [aRR]: 0.85 [CI: 0.28, 2.55]). There was no significant difference in the frequency of appropriate PrEP use between the arms (68.2% vs. 59.1% in Targeted vs. Universal, respectively) (aRR: 1.03 [CI: 0.96, 1.10]). Conclusions Given comparable maternal HIV incidence and PrEP uptake in Universal and Targeted approaches, and the simplicity that universal PrEP offers, our findings suggest that universal PrEP counselling is optimal for integrating PrEP in MCH systems.


I N T R O D U C T I O N
During the pregnancy and breastfeeding periods, there is an increased risk of HIV acquisition [1][2][3]. Women who acquire HIV during these periods are at higher risk for vertical transmission than those with chronic HIV infection [4][5][6][7]. Pre-exposure prophylaxis (PrEP) is an effective, female-controlled option for HIV prevention recom-mended for use in pregnant and breastfeeding populations [8][9][10][11][12][13][14][15].
While studies have demonstrated the feasibility and acceptability of PrEP in maternal and child health (MCH) clinics, implementation questions remain [16][17][18][19][20][21]. Introducing PrEP in MCH clinics presents challenges to overburdened healthcare workers (HCWs) [22,23] and requires adaptations in HIV testing, PrEP counselling, dispensing and adherence counselling. Importantly, women need to understand their risk of acquiring HIV to make informed decisions about PrEP. Minimizing unnecessary PrEP use among women at low risk avoids side effects or foetal exposure and conserves PrEP resources for those at high risk. Implementation models that maximize PrEP use among women most at risk for HIV while minimizing use among low-risk women have not been studied.
The World Health Organization recommends a risk-guided approach for HIV prevention as part of prevention-of motherto-child transmission (PMTCT) programmes [11]. Identified risk factors for HIV acquisition in pregnancy [24] could be used to screen women based on HIV risk. Risk-guided approaches may increase service efficiency by limiting who receives PrEP counselling and offer [25]; moreover, riskguided counselling could improve risk perception and PrEP acceptance and continuation [26]. Conversely, risk-guided approaches could increase stigma or bottlenecks due to increased counselling time among "at-risk" women. A universal model of counselling that frames reasons to consider PrEP (such as partner HIV status) to all pregnant women after which women decide whether to initiate PrEP may decrease stigma. However, universal PrEP offers may lead to either over-or under-use of PrEP depending on how clearly women understand their risk following general counselling.
It is unclear whether a risk-guided model would reduce HIV incidence and increase appropriate PrEP decisions than universally offering PrEP. To address this question, we conducted a cluster-randomized trial (cRCT), the PrEP Implementation for Mothers in Antenatal Care (PrIMA) study, to compare Universal and Targeted (risk-guided) approaches to PrEP delivery. We hypothesized that Targeted PrEP delivery would result in lower HIV incidence and more appropriate PrEP decisions.

M E T H O D S 2.1 Study design
The PrIMA study was a cRCT evaluating two models of PrEP delivery among pregnant women attending MCH clinics (Clinical Trials.gov #NCT03070600). The study protocol has been described [27]. Briefly, 20 public MCH clinics in Siaya or Homa Bay counties in Kenya were randomized to Universal or Targeted PrEP counselling using restricted randomization, stratified by antenatal care clinic (ANC) volume and county. Enrolment occurred between 15 January 2018 and 31 July 2019, and all women had the chance to be followed through 9 months postpartum. MCH clinics were eligible for inclusion if they had >350 HIV-negative annual ANC clients and offered postnatal care. Study facilities were selected in collaboration with the County Ministry of Health (MoH) to ensure geographic distribution. Assuming a coefficient of variation (k) of 0.2, with 10 clinics per cluster and 200 women enrolled per facility, the study had 80% power to detect a two-fold difference in annual HIV incidence.

Universal arm
At Universal arm clinics, after informed consent, participants received PrEP counselling using a standardized script listing risk factors for HIV and considerations for PrEP use, after which participants decided whether to initiate PrEP.

Targeted arm
At Targeted arm clinics, participants underwent an HIV risk assessment, adapted from Kenyan National AIDS and STI Control Programme (NASCOP) guidelines and an HIV risk assessment tool shown to predict HIV risk in pregnant and postpartum women (Pintye tool) [24]. In the Targeted arm, those at high risk received standardized PrEP counselling and offer. Although PrEP offer in the Targeted arm was riskguided, any woman who asked for PrEP was provided with PrEP regardless of risk status. The Pintye HIV risk assessment tool had an area under the curve of 0.76 to predict HIV incidence in pregnancy/postpartum [24]; score: 1 point per lifetime sexual partner, 6 points if the sexual partner's HIV status is positive or unknown and 5 points for syphilis positive [24]. Under NASCOP guidelines, anyone with any of the following in the last 6 months was eligible for PrEP: transactional sex, sexually transmitted infection (STI) diagnosed or treated, forced sex, physically assaulted, including by their sexual partner, shared needles during intravenous drug use or used post-exposure prophylaxis more than twice [10]. Participants with a score of ≥6 on the assessment tool or any NASCOP risk factor were considered high risk. Targeted arm participants were offered HIV self-test kits (HIVST) for use with partners to provide information on partner HIV status to guide PrEP decision-making. Women were counselled that they should not accept and/or offer HIVST to their partners if they had any concerns about physical, emotional or other types of repercussions from offering HIVST to their partners.
Women were asked at subsequent study visits about the partner HIVST results and about whether they had changed their decision about whether to use, or not use, PrEP.

Eligibility criteria
Eligibility criteria included: pregnant at enrolment, HIV negative (documented from MCH records during the ANC visit), not currently using PrEP, ≥ 15 years old, tuberculosis negative, planned to reside in the region for ≥1-year postpartum, planned to receive postnatal care at the study facility and not enrolled in any other studies. In both arms, those with creatinine clearance (CrCl) ≤50 ml/minute or hepatitis B surface antigen (HBsAg) positivity were ineligible for PrEP per NASCOP guidelines [10].

Enrolment and follow-up
At enrolment, questionnaires were administered on sociodemographic characteristics, mental health (PHQ-2) [28], intimate partner violence (IPV) using the HITS scale [29], PrEP knowledge and partner HIV status. In the Universal arm, participants underwent HIV risk assessment after they received PrEP counselling and had decided whether to accept PrEP. Gestational age at enrolment was assessed using last menstrual period (97.9%) or fundal height (2.1%). Syphilis testing was conducted through rapid plasma reagin (RPR) during the first ANC visit and results were abstracted from medical records. If no syphilis data were available, the study team provided testing using SD Bioline HIV/Syphilis lateral flow Duo Test Kits.
Participants were seen at monthly ANC visits, followed by postnatal visits at 6 weeks, 14 weeks, 6 months and 9 months postpartum. Visits aligned with Kenya MoH recommendations for antenatal and infant immunization visits. Self-reported PrEP adherence was assessed. At each follow-up visit, participants had blood collected for HIV testing and those on PrEP had dried blood spots (DBS) collected for assessment of drug levels.
Between June and October 2018, the Kenya MoH introduced the offer of partner HIVST to women attending MCH. Information on HIVST including: the offer of HIVST to partner, partner uptake and results were collected. All data were collected using password-protected tablets and uploaded daily to encrypted Research Electronic Data Capture (REDCap) servers [30].

Primary outcomes
Maternal HIV incidence and "appropriate PrEP use" were the primary outcomes. HIV incidence was defined as confirmed maternal HIV infections per 100 person-years of follow-up. Incident HIV infections were compared between arms using generalized estimating equations (GEE) with a Poisson link. Appropriate PrEP use was defined as the proportion of highrisk (either NASCOP or Pintye tools) accepting PrEP and lowrisk declining PrEP and was compared between arms using GEE with a Poisson link. Independent correlation structures with robust standard errors were used for all GEE models. All analyses included clustering by the facility. Adjusted models included baseline high-risk HIV status and marital status.

Secondary outcomes
PrEP acceptance, initiation, adherence, and duration, and partner HIV status (at 9 months postpartum) were secondary outcomes. PrEP acceptance was defined as participants who accepted PrEP at any visit. PrEP confirmation visit was defined as participant-report of swallowing PrEP pills at visits after PrEP acceptance, with the PrEP initiation date defined as the median date between the PrEP acceptance and PrEP confirmation visits. At the PrEP confirmation visit, self-reported PrEP adherence was dichotomized as no missed doses versus any missed doses in the past 30 days. The PrEP duration was defined as the time between the PrEP initiation date and discontinuation or study end [33]. The proportion of women who accepted and used PrEP and self-reported adherence was compared between arms using GEE with a Poisson link. Proportions of partner HIV status unknown and change in partner HIV status knowledge by the study end were compared between arms using GEE with a Poisson link. Mean PrEP duration was compared between arms using GEE with a Gaussian link.
All analyses were conducted using Stata SE 17.0 (Stata-Corp, College Station, TX).

External oversight
An External Advisory Panel (EAP) met at study initiation and mid-way through follow-up to evaluate safety and endpoints. At the mid-way evaluation, baseline differences were noted between trial arms. The EAP advised that analyses be adjusted for key differences at baseline (marital status and HIV risk). Two Community Advisory Boards, one in Homa Bay and one in Siaya, met at least annually to review study progress and to make recommendations.

R E S U LT S
The study team assessed 45 facilities for inclusion, 19 of which did not meet the inclusion criteria, and six of which were excluded based on recommendations of County MoH.

Baseline characteristics and comparison by randomization arm
Of 8427 women screened for enrolment, 4447 women were enrolled (2250 Universal arm and 2197 Targeted arm) ( Figure 1 and Table S1). The median age of participants was 24.0 years (interquartile range [IQR] 20.9, 28.3). More than half of the participants were < 25 years old (57.3%), and most (84.8%) were currently married. Median educational attainment was 10 years (IQR 8, 12) and 14.9% of women were employed. Just under half (47.7%) reported living in crowded environments. The median gestational age at enrolment was 24 weeks (IQR 20, 30) and the majority (74.4%) of participants had been pregnant previously. Overall, 9.5% of women had symptoms of moderate-to-severe depression (PHQ2 ≥3) and 7.8% reported IPV (HITS score ≥10). Overall, 42.3% of participants met high-risk criteria (Table 1). Women in the Targeted arm clinics were more likely to be married, know someone on PrEP, have depressive symptoms and be at high risk for HIV acquisition (51.6% vs. 33.3% Universal arm) than women in the Universal arm.

HIVST uptake in Targeted arm
In the Targeted arm, 1384 (63.5%) accepted HIVST for partner HIV testing ( 15 women whose partner was newly determined to be HIV positive or indeterminate, five (33%) had initiated PrEP prior to HIVST results and five (33%) elected to start PrEP after HIVST results, and five (33%) did not start PrEP. Because the NASCOP implemented HIVST in MCH over the course of the study, we ascertained HIVST acceptance in both study arms. However, few women in the Universal arm (0.93%, [21/2250]) reported accepting HIVST through MCH due to stockouts, lack of systematic offer and low awareness.

Participant risk characteristics at 9 months postpartum
Using new information available at the end of the study to estimate risk status, 30.8% of women overall would be classified as high risk, 637/2032 (31.3%) in the Targeted arm and 654/2156 (30.3%) in the Universal arm (Table 4). Thus, the proportion of "high risk" women decreased from baseline (51.6%) to 9 months (31.3%) (p = 0.001) in the Targeted arm and from 33.3% to 30.3% in the Universal arm (p = 0.26). With the significant decrease in the proportion of women defined as being in the "high risk" category at 9 months postpartum within the Targeted arm, there was no longer an increased relative risk of a participant being in the "high risk" category at 9 months postpartum between the Tar-

D I S C U S S I O N
In this cRCT, we found that a risk-guided PrEP offer (Targeted) was not superior to a Universal PrEP offer, based on appropriate PrEP decision and HIV incidence, among women attending MCH in high HIV prevalence regions of Kenya. The frequency of appropriate PrEP decisions did not differ significantly between the study arms, HIV incidence was low in both arms and PrEP continuation was high. These results demonstrate that PrEP decision-making was not improved by risk-guided counselling. Universal PrEP offer following simple standard counselling resulted in a comparable proportion of women making appropriate PrEP decisions as the risk-guided approach.
Maternal HIV incidence in this cohort was approximately seven-fold lower than in a prior study, of pregnant and postpartum women in western Kenya conducted between 2011 and 2013 (maternal HIV incidence of 2.31/100 py) [34]. Lower maternal HIV incidence likely reflects wider population antiretroviral therapy use and PrEP use in this maternal cohort. The low maternal HIV incidence that we observed is encouraging and provides the first-of-its-kind data on HIV incidence in MCH clinics providing PrEP. Without PrEP, maternal HIV incidence remains a leading contributor to new paediatric HIV infections in high HIV prevalence settings [4,5]. Our data support efforts to integrate PrEP into PMTCT programmes.
We found that almost two-thirds of women made appropriate decisions regarding PrEP use in either study arm. In a qualitative study of HCW perspectives on delivering PrEP to pregnant and postpartum women, it was noted that risk-guided counselling took time and uncovered issues that were sometimes challenging or uncomfortable to discuss [35]. Women may prefer not to discuss risk factors with health workers because such discussions may be stigmatizing or uncomfortable [36,37]. Comparable PrEP uptake in the Universal arm suggests that the general counselling was sufficient for women to privately deliberate their PrEP decision. Among low-risk women, a slightly higher proportion of PrEP uptake in the Universal arm (12.3% vs. 6.1%, p: 0.082) may reflect undisclosed risk factors, imprecision in the assessment of risk or unclear messaging about PrEP that could be addressed in counselling approaches.
Our results suggest a Universal approach may be the simplest and most effective option for PrEP counselling in MCH as no screening is required to reach similar levels of appropriate PrEP use and HIV incidence as a risk-guided strategy. A Universal PrEP offer approach lends itself to group counselling strategies and may allow for task shifting to reduce the burden on nurses. Universal PrEP offer allows women to control all aspects of the PrEP cascade, including assessing their own risk and deciding whether PrEP is the right option. Universal PrEP offer may reduce stigma as it is being generally discussed and not targeted to certain women. Universal PrEP counselling also increases community awareness of PrEP, which can influence PrEP decision-making and reduce stigma [38,39]. Our results also demonstrate low rates of ineligibility due to CrCl ≤50 ml/minute or HBSAg positivity suggesting that universal screening for CrCl or HBSAg is unnecessary [40].
Our Targeted arm strategy included the provision of HIVST for partner testing. We found high uptake (>60%) of HIVST with very high levels of partner use (>80%). The greatest drop off in HIVST use was at the point of HIVST acceptance by participants, when participants were advised not to accept or offer HIVST to their partners if there were concerns about IPV or negative repercussions. Based on this, additional research is needed to identify strategies to support participants at risk of IPV in partner HIV testing. Almost 100% of women whose partner tested reported seeing the results with their partner. In the Targeted arm, the proportion of women who did not know their partner's status declined from >40% to 18.8% by the end of the study, the majority of cases identified an HIV-negative partner and decreased the likelihood of being classified "high risk." At enrolment, some women in the Targeted arm classified as high risk due to unknown partner status correctly speculated that their partner was HIV negative and declined PrEP. HIVST helped women who initiated PrEP discontinue PrEP if they found their partner was negative. Others with a newly identified HIV-negative partner may have continued PrEP due to having other partners or suspicions of infidelity. The HIVST uptake and impact in the Targeted arm suggests that offering HIVST in MCH clinics for partner testing along with a Universal PrEP offer could be an important strategy.
Future implementation science research will be useful to refine strategies for Universal PrEP counselling in MCH including determining whether task shifting of components of the PrEP delivery cascade is appropriate [21]. Similarly, research will be needed to understand approaches to support the implementation of new long-acting PrEP formulations during pregnancy and breastfeeding once these regimens are approved for use in this context. This study has strengths and limitations. This was a large multisite cRCT with high retention (94%). We included HIV PCR confirmatory testing for all potential new maternal HIV infections [32]. Low HIV incidence in both arms limited power for comparisons of that primary outcome; however, the similarity in HIV incidence in both arms (0.38 and 0.31/100 person-years) suggests that meaningful differences are unlikely. Changing MoH policies and the COVID-19 pandemic also affected study operations. MoH-led HIVST rollout could have influenced participant knowledge of their partners' HIV status and PrEP acceptance overall; however, only 0.93% of women in the Universal arm reported receiving HIVST, demonstrating limited programmatic rollout. Participant retention, outcome ascertainment and health-seeking behaviour were minimally impacted by COVID-19-related restrictions. Finally, our observed rates of PrEP adherence and persistence could have been influenced by efforts to optimize study retention, and our estimates of PrEP adherence rely on self-report, which can overestimate adherence.

C O N C L U S I O N S
The results of the PrIMA study suggest that incorporating HIV-risk screening to target PrEP offer to high-risk women in ANC does not influence HIV incidence or appropriate PrEP uptake compared with universal PrEP counselling to all women receiving antenatal care.
JCD and LG verified the data and analysis. JCD and GJS drafted the manuscript. All authors critically reviewed the manuscript.

A C K N O W L E D G E M E N T S
The authors would like to gratefully thank the study participants and PrIMA staff for their time and contributions. We thank the Kenyan Ministry of Health nationally, the Homa Bay and Siaya County Ministries of Health, and the facility heads and in-charges for their collaboration with this study.

F U N D I N G
Funding for this project was provided by the National Institutes of Health, National Institute of Allergy and Infectious Disease (GJS-R01AI125498) and Eunice Kennedy Shriver National Institute of Child Health & Human Development (GJS-R01HD094630; JP-R01HD100201). The team was supported by the University of Washington's Center for AIDS Research Behavioral Sciences Core and Biometrics Core (P30AI027757) and the Global Center for the Integrated Health of Women, Adolescents, and Children (Global WACh). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

S U P P O R T I N G I N F O R M AT I O N
Additional information may be found under the Supporting Information tab for this article: Table S1: Distribution of demographic characteristics of women screened and enrolled in the study